Though the club was billed as a discothèque, meaning only recordings with no bands, the Whisky a Go Go opened with a live band led by Johnny Rivers and a short-skirted female DJ spinning records between sets from a suspended cage at the right of the stage. When, in July 1965, the DJ danced during Rivers' set, the audience thought it was part of the act and the concept of Go-Go dancers in cages was born. Rivers rode the Whisky-born "go-go" craze to national fame with records recorded partly "live at the Whisky." The Miracles recorded the song "Going to a Go-Go" in 1966 (which was covered in 1982 by The Rolling Stones), and Whisky a Go Go franchises sprang up all over the country.

In 1966, the Whisky was one of the centers of the Sunset Strip police riots. The club was often in conflict with the City of Los Angeles, which once ordered that the name be changed, claiming "whisky" was a bad influence. It was the "Whisk?" for a while.

Arguably, the rock and roll scene in Los Angeles was born when the Whisky started operation. From rock to punk to heavy metal, the club stood at the forefront of many musical trends.

Arthur Lee of Love immortalized the Whisky in the song Maybe the people would be the times or Between Clark and Hilldale. "Here they always play my songs," he would sing on the side two opener of Forever Changes. The Whisky was located on the strip between the streets Clark and Hilldale

In the mid-1970s, The Whisky was the home of The Cycle Sluts, a cabaret show. However, Kim Fowley was able to persuade the management to return the club to rock music. On Thanksgiving Day, 1976, two Fowley-managed bands, Venus & The Razorblades and The Quick, began a four-night stand. Thanks to the club being filled, the Whisky continued on as a rock 'n' roll club.

The Whisky fell on hard times once the first flush of punk rock lost steam, and closed its doors in 1982. It reopened in 1986 as a "four-wall", a venue that could be rented by promoters and bands. Although a few booths remain on the perimeter, the interior has mostly been transformed into a bare, seatless space where the audience is forced to stand throughout the performances. A few sets of tables and chairs remain in the upstairs area, but these are often roped off as a "VIP" section, reserved for special guests of the bands, record executives, etc. Against this new economic backdrop, a number of hard rock and metal bands, including Guns N' Roses and Metallica, rose to prominence in the 1980s.